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Substituted heterocyclic acyl-tripeptides useful as thrombin receptor modulators

a technology of acyltripeptides and thrombin receptors, which is applied in the direction of drug compositions, peptide/protein ingredients, extracellular fluid disorders, etc., and can solve problems such as the need to adjust dosages

Inactive Publication Date: 2004-04-01
ORTHO MCNEIL PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.

Method used

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  • Substituted heterocyclic acyl-tripeptides useful as thrombin receptor modulators
  • Substituted heterocyclic acyl-tripeptides useful as thrombin receptor modulators
  • Substituted heterocyclic acyl-tripeptides useful as thrombin receptor modulators

Examples

Experimental program
Comparison scheme
Effect test

example 2

N-(5-Bromopyridin-3-yl-carbonyl)-cyclohexylalanyl-argininyl-phenylalanine Amide (2)

[0081] 11

[0082] Fmoc-phenylalanine amide (3.87 g, 10 mm) was stirred in ACN (100 mL) and DEA ( 5 mL) was added and stirred at RT for 1 hr. The solution was evaporated in vacuo to an oil, which was triturated 3.times. with hexane (100 mL) and dissolved in ACN (100 mL); Fmoc-Arg(PMC)-OH (6.63 g, 10 mm) and HOBT (1.53 g, 10 mm) were added, followed by DCC (4.1 g, 20 mm) and solution was stirred at RT. The urea by-product was filtered and the filtrate was evaporated in vacuo to an oil, which was triturated 3.times. with hexane (100 mL). The crude product was stirred in ACN (100 mL) and DEA (5 mL) was added and stirred at RT for 1 hr. The solution was evaporated in vacuo to an oil, which was triturated 3.times. with hexane (100 mL) to a solid. This dipeptide was combined in ACN (100 mL) with Fmoc-Cha-OH (3.93 g, 10 mm) and HOBT (1.53 g, 10 mm) and then DIC (2.52 g, 20 mm) was added and reaction stirred at ...

example 3

[0083] As a specific embodiment of an oral composition, 100 mg of the compound 1 of Example 1 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.

[0084] BIOLOGY

[0085] The compounds of the present invention modulate platelet activation induced by thrombin's proteolytic cleavage of its platelet surface receptor, and thereby activate / inhibit platelet aggregation. Compounds that exhibit agonist activity may be expected to aid in wound healing and tissue repair, while antagonist compounds may be useful in treating platelet-mediated thrombotic disorders such as arterial and venous thrombosis, acute myocardial infarction, reocclusion following thrombolytic therapy and angioplasty, and a variety of vaso-occlusive disorders.

example 4

[0086] IN VITRO THROMBIN RECEPTOR BINDING ASSAY.

[0087] CHRF membranes (Jones, Biochim. Biophys. Acta 1992, 1136, 272) are thawed from -70.degree. C., centrifuged at maximum speed for 5 min, washed twice with binding buffer (50 mM HEPES containing 5 mM MgCl.sub.2 and 0.1% BSA), and re-suspended in binding buffer (25 g / 100 mL). 100 l membranes are added to the 24-Wallac plates and delivered to the Tomtech apparatus. In a typical experiment, 6 l of samples (from a 125 g / mL intermediary plate, 20% DMSO) and 44 l buffer are delivered to the plates (final conc. of compounds is 3.7 g / mL, 0.6% DMSO). Similarly, 6 l 20% DMSO and 44 l buffer are delivered to both column 1 (NSB) and column 12 (TB). 10 l Ser-pFPhe-Har-Leu-Har-Lys-Tyr-NH.sub.2 (721-40; 500 M i n deionized water) is added to column 1. 50 l tritiated 721-40 (specific activity 46 Ci / mmol) is added to all the wells. The plates are mixed well for 20 seconds, incubated for 30 min, and then harvested with 10 mM HEPES / 138 mM NaCl using ...

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Abstract

The invention is directed to substituted heterocyclic acyl-tripeptides useful as thrombin receptor modulators, their use in wound healing and preventing platelet aggregation. Pharmaceutical compositions comprising the substituted heterocyclic acyl-tripeptides of the present invention and methods of treating conditions mediated by the thrombin receptor are also disclosed.

Description

[0001] The present application is a continuation-in-part of Ser. No. 09 / 444,327 that was filed on Nov. 19, 1999 (hereby incorporated by reference herein) which claims priority from provisional patent application Serial No. 60 / 112,313, filed on Dec. 14, 1998.BACKGROUND OF THE INVENTION[0002] Thrombin is an important serine protease in hemostasis and thrombosis. One of the key actions of thrombin is receptor activation. A functional human thrombin receptor (TR), cloned by Coughlin in 1991 (T.-K. Vu, Cell 1991, 64, 1057), was found to be a member of the G-protein coupled receptor (GPCR) superfamily. The receptor activation putatively occurs by N-terminal recognition and proteolytic cleavage at the Arg-41 / Ser-42 peptide bond to reveal a truncated N-terminus. This new receptor sequence, which has an SFLLRN (Ser-Phe-Leu-Leu-Arg-Asn) N-terminus acting as a tethered ligand to recognize a site on the receptor, can trigger activation and signal transduction leading to platelet aggregation. Pe...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/00C07K5/02C07K5/087C07K5/117
CPCA61K38/00C07K5/1024C07K5/0812C07K5/0202A61P35/00A61P7/02A61P9/10
Inventor MCCOMSEY, DAVID F.MARYANOFF, BRUCE E.HAWKINS, MICHAEL J.
Owner ORTHO MCNEIL PHARM INC
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